- Email: [email protected]
The cognitive principle challenges clonal selection
viewpoint 34 Bauer, D.C., Mathies, M.J. and Stavitsky, A.B. (1%3i
J. Exp. Med. 117, 889-907 35 Hurlimann, J., Wakefield, J.D. and Thorbecke, G.J. (1967) in Germinal Centers in Immune Responses (C©ttier, H., Odartchenko, N., Schindler, R. and Congdon, C.C., eds), pp. 225-233, Springer-Verlag
36 Rothstcin, I l.. and Gefter, M.L. (1983) Mol. lmmunol. 20, 161-168 37 Pink, J.R.I.. md Askonas, B.A. (1974) Eur. ]. Imrnunol. 4, 426-43O 38 Mitchell, G.F., Grument, F.C. and McDevitt, H.O. (1972/.I. I-.xp. Med. 135, 126-135
The cognitive principle challenges clonal selection Irun R. Cohen Here, Irun Cohen argues that the clonal selection paradigm is no longer a convenient paradigm for organizing thinking about the immune system. He contends that most immunologists now investigate questions for which the clonal selection paradigm makes no provision and that one of its major tenets is contradicted by the prevalence of natural autoimmunity. Instead, he proposes a cognitive paradigm. Mental paradigms are models that simplify complexity, ideas that help to make sense out of the infinitely complex continuum which is reality. No idea can represent reality as it is. A paradigm merely represents a fragment of reality in a way that allows the mind to deal with it: it encodes a part of the world to the mind's specifications. A paradigm is formed and retained because it is useful, not because it is reaP. A scientific paradigm marks out a conceptual territory for exploration by observation and experimentation. It establishes a world view that defines which questions are worth studying and what answers might be expected. Thus, the prevailing paradigm will bias the way the scientist views and interprets the results of experiment. Certainly, the prevailing paradigm can determine the experiment's publishability. Paradigms must be taken seriously: they influence what we see and what we say. An antiquated paradigm is a hazard. The paradigm which, for over three decades, has organized immunological thinking is clonal selection-'. The clonal selection paradigm holds the antigens responsible for organizing the immune system; only those lymphocyte clones bearing receptors that match the antigens encountered by the individual flourish. To avoid autoimmunity, recognition of self is forbidden. Thus does the clonal selection paradigm explain the specificity of adaptive immunity and the tolerance for antigens of the self. The world view inculcated by the clonal selection paradigm has led many immunologists to believe that the primary function of the immune system is to distinguish between the self and the foreign. A textbook by Jan Klein embodies this belief in its title - Immunology: The Science of Self-Nonself
Discrimination 3. The clonal selection paradigm identifies autoimmune disease as an accident of self recognition origi-
nating from a random mutation of a lymphocyte receptor or from a failure to delete a forbidden clone 4. Autoimmune lymphocytes arise by chance and express chance specificity; autoimmune diseases should have clinical expressions dictated by chance. Burnet makes the point clear: 'It is of the essence of our approach to immunity that no two cases of autoimmune diseases should be the same '4. Flaws in the clonal selection paradigm Progress in immunology appears to have rendered the clonal selection paradigm incomplete, if not obsolete; true, it accounts for the importance of clonal activation, but it fails to encompass, require, or explain most of the subjects being studied by immunologists today: antigen processing and presentation, the structure and function of major histocompatibility complex (MHC) molecules, multicellular interactions, restrictions in T-cell receptor and immunoglobulin gene usage, superantigens, cytokine functions and networks, suppression, and anti-idiotypes. More importantly, what we have learned about autoimmunity directly contradicts a major corollary of the clonal selection paradigm: autoimmunity is not an aberration, but is a property of all healthy immune systems s'';. Moreover, the particular self-antigens recognized by natural autoimmune T and B cells are not random accidents but are a limited and predictable set of antigens (Table 1). Indeed, a particular class of B cells, the B-1 (formerly known as CD5) B cells, appears to specialize in making natural autoantibodies r. In contradiction of Burnet's assertion 4, pathological autoimmunity, too, is highly structured: there are only a few dozen autoimmune diseases, each immunologically quite typical 8. Indeed, a large majority of the patients can probably be accounted for by less than ten different diseases. Thus, the
© 1992, Elsevier Scienc( Publishers Ltd, UK.
Immunology Today
441
Vol
o92
Table 1. Natural autoimmunity demonstrable in healthy individuals
Autoantibodies 6 Cell membrane components:
[32-microglobulin, spectrin, band 3 protein, secretory component.
Intracellular components:
Actin, tubulin, myosin, keratin, DNA, myoglobulin, cytochrome c, collagen, myelin basic protein, protamine.
Plasma proteins:
Albumin, transferrin, IgG.
Cytokines and hormones:
Interferons, interleukin la, tumor necrosis factor, insulin, thyroglobulin.
T cells
Thyroglobulin 23, acetylcholine receptor 24, myelin basic protein 2s, hsp65 (Ref. 26), insulin 27.
expression of pathological autoimmunity, like the expression of benign autoimmunity, is not accidental. In a follow-up paper in next month's Immunology Today9, the relationship between natural autoimmunity and autoimmune disease will be discussed; here, I simply note that the existence of natural autoimmunity negates a central principle of the clonal selection paradigm and suggests that the evolutionary aim of the immune system is not to distinguish between self and nonself. In fact the aim of the immune system should escape no one; it is to enhance fitness.
Immunological fitness Fitness is the term used by evolutionary biologists to describe success in surviving to generate fit offspring 1°. Children born without immune systems and adults who acquire defective immune systems, unless treated by very special measures, die of infection. Hence, it may be concluded that the forces most consequential in forging the immune system are those exerted by infectious agents. (This assertion is true even if some infectious agents like Treponema pallidum or Group A Streptococci may make us sick with autoimmunity.) Therefore, the immune system enhances fitness by preventing death from infection. To carry out this function, the immune system (like any other adaptive system) must solve three problems: (1) the signal/noise problem, or how to focus recognition; (2) the context problem, or when to act; and (3) the response problem, or how to choose the most suitable set of immune effects.
The signal~noiseproblem Any biological macromolecule can be seen as a conglomerate of potentially antigenic epitopes.
Immunology Today
Theoretically, if a minimal T-cell epitope is a processed peptide of nine amino acids 11, then any protein could have as many overlapping epitopes as it has amino acids, minus eight. B-cell epitopes are created by the mosaic of conformational features of the protein. A standard bacterium with 10 4 genes could confront the immune system with perhaps 10 6 potential epitopes, at least theoretically. Theoretically too, the receptor repertoire of the immune system should be able to muster lymphocyte clones to recognize all of them. Thus, inherent in any immune response is noise, a paralyzing degree of polyclonal activation. Indeed, some parasites neutralize the immune system by activating it polyclonally 12. The large numbers of potential epitopes present on every antigen could never be allowed a free hand in selecting all potentially reactive lymphocyte clones. The system must have discriminating filters. To make sense out of the input is to filter out the inessential noise and to concentrate on a manageably small part of reality. Focusing creates signal.
The contextproblem But to rescue a signal from noise is not sufficient for fitness; we have to know the context in which the signal arrives. Context bestows meaning. The context tells us if the gun we see is likely to be a toy or a weapon, if it is theater or murder. A processed peptide presented in the pocket of an MHC molecule may constitute an antigenic epitope for a T cell 11, but fitness cannot be promoted without more information. Has the epitope originated from an infection or not? An epitope in the context of infection might best be attacked; the same epitope in the context of repose (no sign of infection) might best be ignored or tolerated. It is not sufficient merely to distinguish whether the antigen is self or foreign: an unnecessary immune response to harmless foreign antigens can incapacitate by allergy; at the very least, such a response can squander limited resources. Appreciation of context is the beginning of wisdom.
The responseproblem Contrary to the world view of the clonal selection paradigm, the immune response is not a monotonic reflex triggered by antigen recognition. Indeed, the nature of the response - its quality, quantity, timing and location - is what gives effective meaning to the recognition. For example, the striking differences between polar lepromatous leprosy, polar tuberculoid leprosy and successful rejection of Mycobacterium leprae are not due merely to recognition or lack of recognition of the microorganism. In all three cases the microbe is recognized by the immune system; the differences, tragic or happy, are a consequence of the types of cells and cytokines activated after recognition 13. A formidable feature of the immune system is the richness of its repertoire of responses. The many and diverse types of B cells, antibodies, T cells and cytokines that create the response repertoire can be seen in textbooks and reviews. The biological outcome of an immune response is determined by adjusting the
442
rot. 13 No. 11 1992
viewpoint response repertoire - what the system can do - to the receptor repertoire - what the system can see. The handiwork of the immune system is the product of the two repertoires. The job of the system is not merely to recognize but to mix-and-match repertoires. A suitable mix-and-match outfits the individual ideally to the occasion. There can be no single response that is appropriate to all that is foreign, and the absence of recognition cannot always be appropriate for all that is like self. The naked epitope cannot tell an inexperienced lymphocyte which type of response is appropriate; information about the context is necessary.
The internal images encoded in the brain function not only to organize the information entering from the external environment; the brain contains a picture of the individual's own body, the neurological homunculus. A common but enigmatic aberration of the brain's image of the self is the phantom limb, the vivid and often painful sensation of the continuing existence of a limb that has been amputated or even of a limb that has been absent from birthUL Study of the phantom limb phenomenon has led some neurologists to conclude that the brain's picture of the self is formed by the activities of networks of neurons ~s. In the next issue '' I shall discuss the immunological homuncuThe cognitive paradigm lus s'~*, the immune system's picture of the self, which Unstructured encounter with antigens as visualized also appears to be encoded in cellular networks. by the original clonal selection paradigm is indifferent By encoding the environment, images internal to the to the problems of focus, context and response. The system define the niche within which the system is fact that the immune system solves these problems sug- designed to act. Bees are born with a hard-wired intergests that we might be better off with another para- nal image of the essential flower and its essential necdigm. I propose that a cognitive paradigm can encom- tar; this internal representation allows the bees to recpass many of the features of the system now studied by ognize and deal with real flowers> . Obviously, the immunologists, features that are beyond the ken of the genes of real flowers have encoded in the structure and chmal selection paradigm. In emphasizing the short- behavior of the flowers an image of the structure and comings of the clonal selection paradigm, I do not behavior of the bees. The internal organizations of the mean to imply that clonal activation of lymphocytes bees and of the flowers endow them, in an abstract does not occur; clonal activation of lymphocytes is a sense, with intentionality; they seek each other. The fact. I argue here that clonal activation is only one el- definition and creation of information by internal red ement in the larger world of immune cognition. resentations, the intentionality of a system, is the cogCognitive paradigms are founded on the idea that nitive principle 14'1~. Note that the word cognitive here does not imply any system which collects and processes information will do its job most efficiently by having an internal consciousness. The human central nervous system representation of its subject ~4'~. Simply put, a cognitive often manifests consciousness; the lymphocytes, the system is a system that extracts information and bees and the flowers never do. Likewise, the property fashions experience out of raw input by deploying of intentionalitv is devoid of personality; the immune information already built into the system; in a sense, a system intends to fight infection not because there cognitive system is one that knows what it should be exists a little man inside it who whispers in its ear, but looking for. This internal information, which precedes because the internal organization of the system is and imposes order on experience, can be seen concep- about fighting infection. The system has evolved to tually as a blueprint for dealing with the world. In the behave that way. Note too that an internal code, like abstract, cognitive systems can be said to behave with any code, is only information. Its existence is indepena sense of direction; their internal organization endows dent of any particular material: a bacterial protein may them with a kind of intentionality~L Cognitive systems, be effectively encoded by a different molecule (a nuthen, are not passive processors or recorders of infor- cleic acid sequence), by a convention (the words 'bacmation; they are designed to seek very particular infor- terial protein'), or even by a function (its being bound by a certain antibody). In fact, the antibody to the mation from the domain in which they operate. The nervous system, too, uses a cognitive strategy of protein is a kind of negative or mirror image of the internal images to structure individual experience ~s. protein. Which code is the correct one depends on its The eye, for example, is not merely a passive recorder utility in the particular context. It is worth digressing to note that, just as the of photons; it is wired to seek edges and contours. Preformed images also operate at the highest neural immune system is adapted to our parasites, our paralevels: anyone who interacts with infants can readily sites are adapted to the immune system. Their life observe that the human brain begins life imprinted depends on it. The open-ended antigenic variation of with an internal picture of the human face. Babies parasites is the parasitic internal image of the effectively soon after birth will gaze intently at human faces, or at open-ended repertoire of antigen receptors. The paraany representation that features eyes and a mouth in a sites' internal image of the host may also include host suitable alignment ('smiley' is universal)C Babies smile antigens and host immune system regulatory molat smiles and cry at frowns, even before they distin- ecules, internal images that enable the parasites to surguish between individual faces. The brain's internal vive in the face of host immunity. Microbial adhesion image of the human face directs the infant to seek out molecules actually encode the microbe's image of the and respond to other humans. This germ-line image is host's anatomy. Whether the host or the parasite is the the foundation for the capacity to learn to recognize, information system or the environment is relative to one's point of view. interact, and bond to other individuals.
Immunology Today 4 4 3
rot.
N,,
i i iiii( ii~Iii!iii:I ~iiiii!ii il! i(
viewpoint Varela, Coutinho and their colleagues too have called attention to the cognitive properties of recognition, learning and memory as fundamental to immune behavior 21,22. My purpose here is to show, however briefly, that the principle of internal images applies to adaptive biological systems generally, be they neurological, ecological or immunological, and to illustrate that a cognitive paradigm can encompass the search for context, the extraction of signal from noise, and the deployment of the response repertoire in the service of fitness characteristic of the immune system.
Epilogue This paper has pointed out the incompleteness of the clonal selection paradigm and has introduced the idea of a cognitive paradigm. A cognitive paradigm for immunology states that the immune system must know how to focus on particular antigens and how to evaluate their context before it actually encounters the antigens; the immune system seeks certain antigens in a certain context. Thus, the cognitive paradigm differs from the clonal selection paradigm in proposing that the immune system is not passively selected by the antigens, it is selective of the antigens; clonal selection is structured by antigen selection. It remains to discuss how antigen selection operates through internal images of infection and of the self (the immunological homunculus). These images in part are encoded in the germ line, refined in the thymus, and primed by mother 9. Irun R. Cohen is at the Dept of Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
References 1 Kuhn, T.S. (1970) The Structure of Scientific Revolutions, University of Chicago Press, 2 edn 2 Burnet, F.M. (1959) The Clonal Selection Theory of Acquired Immunity, Cambridge University Press 3 Klein, J. (1982) Immunology: the Science of Self-Nonself
Immunology Today
( ....
Discrimination, John Wiley, New York 4 Burnet, F.M. (1969) Self and Not-Self, Cambridge University Press 5 Cohen, I.R. (1991) in Molecular Autoimmunity (Talal, N., ed.), pp. 437-453, Academic Press 6 Avrameas, S. (1991) Immunol. Today 12, 154-159 7 Casali, P. and Nottkins, A.L. (1989) Annu. Rev. Immunol. 7, 513-535 8 Shoenfeld, Y. and Isenberg, D. (1989) The Mosaic of Autoimmunity, Chp. 2, Elsevier 9 Cohen, I.R. Immunol. Today (in press) 10 Dawkins, R. (1982) The Extended Phenotype pp. 179-194, Oxford University Press 11 Falk, K., R6tzschke, O., Stevanovic, S., Jung, G. and Rammensee, H-G. (1991) Nature 351,290-296 12 Grossman, Z., Greenblatt, C. and Cohen, I.R. (1986) J. Theoret. Biol. 121,129-139 13 Bloom, B.R., Modlin, R.L. and Salgame, P. (1992) Annu. Rev. Immunol. 10, 453-488 14 de Mey, M. (1982) The Cognitive Paradigm, D. Reidel Publishing Co. 15 Young, J.Z. (1988) Philosophy and the Brain, Oxford University Press 16 Dennett, D. (1990) The Intentional Stance, MIT Press 17 Bryant, P.E. (1991) Nature 354, 19 18 Melzack, R. (1992) Sci. Am. 266, 90-96 19 Cohen, I.R. and Young, D.B. (1991) Immunol. Today 12, 105-110 20 Gould, J.L. and Gould, C.G., The Honey Bee, Chp. 9, Scientific American Library 21 Varela, F.J. and Coutinho, A. (1988) in Doing Science, The Reality Club (Brockman, J., ed.), pp. 238-256, Prentice Hall Press 22 Varela, F.J. et al. (1988) in Theoretical Immunology. Part Two, Vol. III (Perelson, A.S., ed.), pp. 359-375, Addison-Wesley 23 Kimura, H. and Davies, T.F. (1991) Clin. Immunol. Immunopath. 58, 195-206 24 Salvetti, M. et al. (1991) Ann. Neurol. 29, 508-516 25 Schluesener, H.J. and Wekerle, H. (1985)J. Immunol. 135, 3128-3133 26 Munk, M.E. etal. (1989) J. Immunol. 143, 2844-2849 27 Naquet, P. et al. (1988) ]. Immunol. 140, 2569-2578
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Vol. 13 No. 11 1992
J. Exp. Med. 117, 889-907 35 Hurlimann, J., Wakefield, J.D. and Thorbecke, G.J. (1967) in Germinal Centers in Immune Responses (C©ttier, H., Odartchenko, N., Schindler, R. and Congdon, C.C., eds), pp. 225-233, Springer-Verlag
36 Rothstcin, I l.. and Gefter, M.L. (1983) Mol. lmmunol. 20, 161-168 37 Pink, J.R.I.. md Askonas, B.A. (1974) Eur. ]. Imrnunol. 4, 426-43O 38 Mitchell, G.F., Grument, F.C. and McDevitt, H.O. (1972/.I. I-.xp. Med. 135, 126-135
The cognitive principle challenges clonal selection Irun R. Cohen Here, Irun Cohen argues that the clonal selection paradigm is no longer a convenient paradigm for organizing thinking about the immune system. He contends that most immunologists now investigate questions for which the clonal selection paradigm makes no provision and that one of its major tenets is contradicted by the prevalence of natural autoimmunity. Instead, he proposes a cognitive paradigm. Mental paradigms are models that simplify complexity, ideas that help to make sense out of the infinitely complex continuum which is reality. No idea can represent reality as it is. A paradigm merely represents a fragment of reality in a way that allows the mind to deal with it: it encodes a part of the world to the mind's specifications. A paradigm is formed and retained because it is useful, not because it is reaP. A scientific paradigm marks out a conceptual territory for exploration by observation and experimentation. It establishes a world view that defines which questions are worth studying and what answers might be expected. Thus, the prevailing paradigm will bias the way the scientist views and interprets the results of experiment. Certainly, the prevailing paradigm can determine the experiment's publishability. Paradigms must be taken seriously: they influence what we see and what we say. An antiquated paradigm is a hazard. The paradigm which, for over three decades, has organized immunological thinking is clonal selection-'. The clonal selection paradigm holds the antigens responsible for organizing the immune system; only those lymphocyte clones bearing receptors that match the antigens encountered by the individual flourish. To avoid autoimmunity, recognition of self is forbidden. Thus does the clonal selection paradigm explain the specificity of adaptive immunity and the tolerance for antigens of the self. The world view inculcated by the clonal selection paradigm has led many immunologists to believe that the primary function of the immune system is to distinguish between the self and the foreign. A textbook by Jan Klein embodies this belief in its title - Immunology: The Science of Self-Nonself
Discrimination 3. The clonal selection paradigm identifies autoimmune disease as an accident of self recognition origi-
nating from a random mutation of a lymphocyte receptor or from a failure to delete a forbidden clone 4. Autoimmune lymphocytes arise by chance and express chance specificity; autoimmune diseases should have clinical expressions dictated by chance. Burnet makes the point clear: 'It is of the essence of our approach to immunity that no two cases of autoimmune diseases should be the same '4. Flaws in the clonal selection paradigm Progress in immunology appears to have rendered the clonal selection paradigm incomplete, if not obsolete; true, it accounts for the importance of clonal activation, but it fails to encompass, require, or explain most of the subjects being studied by immunologists today: antigen processing and presentation, the structure and function of major histocompatibility complex (MHC) molecules, multicellular interactions, restrictions in T-cell receptor and immunoglobulin gene usage, superantigens, cytokine functions and networks, suppression, and anti-idiotypes. More importantly, what we have learned about autoimmunity directly contradicts a major corollary of the clonal selection paradigm: autoimmunity is not an aberration, but is a property of all healthy immune systems s'';. Moreover, the particular self-antigens recognized by natural autoimmune T and B cells are not random accidents but are a limited and predictable set of antigens (Table 1). Indeed, a particular class of B cells, the B-1 (formerly known as CD5) B cells, appears to specialize in making natural autoantibodies r. In contradiction of Burnet's assertion 4, pathological autoimmunity, too, is highly structured: there are only a few dozen autoimmune diseases, each immunologically quite typical 8. Indeed, a large majority of the patients can probably be accounted for by less than ten different diseases. Thus, the
© 1992, Elsevier Scienc( Publishers Ltd, UK.
Immunology Today
441
Vol
o92
Table 1. Natural autoimmunity demonstrable in healthy individuals
Autoantibodies 6 Cell membrane components:
[32-microglobulin, spectrin, band 3 protein, secretory component.
Intracellular components:
Actin, tubulin, myosin, keratin, DNA, myoglobulin, cytochrome c, collagen, myelin basic protein, protamine.
Plasma proteins:
Albumin, transferrin, IgG.
Cytokines and hormones:
Interferons, interleukin la, tumor necrosis factor, insulin, thyroglobulin.
T cells
Thyroglobulin 23, acetylcholine receptor 24, myelin basic protein 2s, hsp65 (Ref. 26), insulin 27.
expression of pathological autoimmunity, like the expression of benign autoimmunity, is not accidental. In a follow-up paper in next month's Immunology Today9, the relationship between natural autoimmunity and autoimmune disease will be discussed; here, I simply note that the existence of natural autoimmunity negates a central principle of the clonal selection paradigm and suggests that the evolutionary aim of the immune system is not to distinguish between self and nonself. In fact the aim of the immune system should escape no one; it is to enhance fitness.
Immunological fitness Fitness is the term used by evolutionary biologists to describe success in surviving to generate fit offspring 1°. Children born without immune systems and adults who acquire defective immune systems, unless treated by very special measures, die of infection. Hence, it may be concluded that the forces most consequential in forging the immune system are those exerted by infectious agents. (This assertion is true even if some infectious agents like Treponema pallidum or Group A Streptococci may make us sick with autoimmunity.) Therefore, the immune system enhances fitness by preventing death from infection. To carry out this function, the immune system (like any other adaptive system) must solve three problems: (1) the signal/noise problem, or how to focus recognition; (2) the context problem, or when to act; and (3) the response problem, or how to choose the most suitable set of immune effects.
The signal~noiseproblem Any biological macromolecule can be seen as a conglomerate of potentially antigenic epitopes.
Immunology Today
Theoretically, if a minimal T-cell epitope is a processed peptide of nine amino acids 11, then any protein could have as many overlapping epitopes as it has amino acids, minus eight. B-cell epitopes are created by the mosaic of conformational features of the protein. A standard bacterium with 10 4 genes could confront the immune system with perhaps 10 6 potential epitopes, at least theoretically. Theoretically too, the receptor repertoire of the immune system should be able to muster lymphocyte clones to recognize all of them. Thus, inherent in any immune response is noise, a paralyzing degree of polyclonal activation. Indeed, some parasites neutralize the immune system by activating it polyclonally 12. The large numbers of potential epitopes present on every antigen could never be allowed a free hand in selecting all potentially reactive lymphocyte clones. The system must have discriminating filters. To make sense out of the input is to filter out the inessential noise and to concentrate on a manageably small part of reality. Focusing creates signal.
The contextproblem But to rescue a signal from noise is not sufficient for fitness; we have to know the context in which the signal arrives. Context bestows meaning. The context tells us if the gun we see is likely to be a toy or a weapon, if it is theater or murder. A processed peptide presented in the pocket of an MHC molecule may constitute an antigenic epitope for a T cell 11, but fitness cannot be promoted without more information. Has the epitope originated from an infection or not? An epitope in the context of infection might best be attacked; the same epitope in the context of repose (no sign of infection) might best be ignored or tolerated. It is not sufficient merely to distinguish whether the antigen is self or foreign: an unnecessary immune response to harmless foreign antigens can incapacitate by allergy; at the very least, such a response can squander limited resources. Appreciation of context is the beginning of wisdom.
The responseproblem Contrary to the world view of the clonal selection paradigm, the immune response is not a monotonic reflex triggered by antigen recognition. Indeed, the nature of the response - its quality, quantity, timing and location - is what gives effective meaning to the recognition. For example, the striking differences between polar lepromatous leprosy, polar tuberculoid leprosy and successful rejection of Mycobacterium leprae are not due merely to recognition or lack of recognition of the microorganism. In all three cases the microbe is recognized by the immune system; the differences, tragic or happy, are a consequence of the types of cells and cytokines activated after recognition 13. A formidable feature of the immune system is the richness of its repertoire of responses. The many and diverse types of B cells, antibodies, T cells and cytokines that create the response repertoire can be seen in textbooks and reviews. The biological outcome of an immune response is determined by adjusting the
442
rot. 13 No. 11 1992
viewpoint response repertoire - what the system can do - to the receptor repertoire - what the system can see. The handiwork of the immune system is the product of the two repertoires. The job of the system is not merely to recognize but to mix-and-match repertoires. A suitable mix-and-match outfits the individual ideally to the occasion. There can be no single response that is appropriate to all that is foreign, and the absence of recognition cannot always be appropriate for all that is like self. The naked epitope cannot tell an inexperienced lymphocyte which type of response is appropriate; information about the context is necessary.
The internal images encoded in the brain function not only to organize the information entering from the external environment; the brain contains a picture of the individual's own body, the neurological homunculus. A common but enigmatic aberration of the brain's image of the self is the phantom limb, the vivid and often painful sensation of the continuing existence of a limb that has been amputated or even of a limb that has been absent from birthUL Study of the phantom limb phenomenon has led some neurologists to conclude that the brain's picture of the self is formed by the activities of networks of neurons ~s. In the next issue '' I shall discuss the immunological homuncuThe cognitive paradigm lus s'~*, the immune system's picture of the self, which Unstructured encounter with antigens as visualized also appears to be encoded in cellular networks. by the original clonal selection paradigm is indifferent By encoding the environment, images internal to the to the problems of focus, context and response. The system define the niche within which the system is fact that the immune system solves these problems sug- designed to act. Bees are born with a hard-wired intergests that we might be better off with another para- nal image of the essential flower and its essential necdigm. I propose that a cognitive paradigm can encom- tar; this internal representation allows the bees to recpass many of the features of the system now studied by ognize and deal with real flowers> . Obviously, the immunologists, features that are beyond the ken of the genes of real flowers have encoded in the structure and chmal selection paradigm. In emphasizing the short- behavior of the flowers an image of the structure and comings of the clonal selection paradigm, I do not behavior of the bees. The internal organizations of the mean to imply that clonal activation of lymphocytes bees and of the flowers endow them, in an abstract does not occur; clonal activation of lymphocytes is a sense, with intentionality; they seek each other. The fact. I argue here that clonal activation is only one el- definition and creation of information by internal red ement in the larger world of immune cognition. resentations, the intentionality of a system, is the cogCognitive paradigms are founded on the idea that nitive principle 14'1~. Note that the word cognitive here does not imply any system which collects and processes information will do its job most efficiently by having an internal consciousness. The human central nervous system representation of its subject ~4'~. Simply put, a cognitive often manifests consciousness; the lymphocytes, the system is a system that extracts information and bees and the flowers never do. Likewise, the property fashions experience out of raw input by deploying of intentionalitv is devoid of personality; the immune information already built into the system; in a sense, a system intends to fight infection not because there cognitive system is one that knows what it should be exists a little man inside it who whispers in its ear, but looking for. This internal information, which precedes because the internal organization of the system is and imposes order on experience, can be seen concep- about fighting infection. The system has evolved to tually as a blueprint for dealing with the world. In the behave that way. Note too that an internal code, like abstract, cognitive systems can be said to behave with any code, is only information. Its existence is indepena sense of direction; their internal organization endows dent of any particular material: a bacterial protein may them with a kind of intentionality~L Cognitive systems, be effectively encoded by a different molecule (a nuthen, are not passive processors or recorders of infor- cleic acid sequence), by a convention (the words 'bacmation; they are designed to seek very particular infor- terial protein'), or even by a function (its being bound by a certain antibody). In fact, the antibody to the mation from the domain in which they operate. The nervous system, too, uses a cognitive strategy of protein is a kind of negative or mirror image of the internal images to structure individual experience ~s. protein. Which code is the correct one depends on its The eye, for example, is not merely a passive recorder utility in the particular context. It is worth digressing to note that, just as the of photons; it is wired to seek edges and contours. Preformed images also operate at the highest neural immune system is adapted to our parasites, our paralevels: anyone who interacts with infants can readily sites are adapted to the immune system. Their life observe that the human brain begins life imprinted depends on it. The open-ended antigenic variation of with an internal picture of the human face. Babies parasites is the parasitic internal image of the effectively soon after birth will gaze intently at human faces, or at open-ended repertoire of antigen receptors. The paraany representation that features eyes and a mouth in a sites' internal image of the host may also include host suitable alignment ('smiley' is universal)C Babies smile antigens and host immune system regulatory molat smiles and cry at frowns, even before they distin- ecules, internal images that enable the parasites to surguish between individual faces. The brain's internal vive in the face of host immunity. Microbial adhesion image of the human face directs the infant to seek out molecules actually encode the microbe's image of the and respond to other humans. This germ-line image is host's anatomy. Whether the host or the parasite is the the foundation for the capacity to learn to recognize, information system or the environment is relative to one's point of view. interact, and bond to other individuals.
Immunology Today 4 4 3
rot.
N,,
i i iiii( ii~Iii!iii:I ~iiiii!ii il! i(
viewpoint Varela, Coutinho and their colleagues too have called attention to the cognitive properties of recognition, learning and memory as fundamental to immune behavior 21,22. My purpose here is to show, however briefly, that the principle of internal images applies to adaptive biological systems generally, be they neurological, ecological or immunological, and to illustrate that a cognitive paradigm can encompass the search for context, the extraction of signal from noise, and the deployment of the response repertoire in the service of fitness characteristic of the immune system.
Epilogue This paper has pointed out the incompleteness of the clonal selection paradigm and has introduced the idea of a cognitive paradigm. A cognitive paradigm for immunology states that the immune system must know how to focus on particular antigens and how to evaluate their context before it actually encounters the antigens; the immune system seeks certain antigens in a certain context. Thus, the cognitive paradigm differs from the clonal selection paradigm in proposing that the immune system is not passively selected by the antigens, it is selective of the antigens; clonal selection is structured by antigen selection. It remains to discuss how antigen selection operates through internal images of infection and of the self (the immunological homunculus). These images in part are encoded in the germ line, refined in the thymus, and primed by mother 9. Irun R. Cohen is at the Dept of Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
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